心血管系统是胚胎发育中最先形成的器官之一, 为机体提供营养成分和氧气。血管发育包括两部分, 一是内皮祖细胞(Angioblast)聚集形成血管原基(Vasculogenesis), 二是从已有血管形成新的血管分支(Angiogenesis)。此后由初级内皮细胞管召集平滑肌细胞形成功能性血管(Vessel maturation)。内皮祖细胞起源途径包括：由Flk1阳性中胚层细胞到成血成血管细胞(Hemangioblast)到血管内皮祖细胞; 或由Flk1阳性中胚层细胞直接到血管内皮祖细胞。Flk1阳性中胚层细胞受到vegf、flk1、cloche、lycat、etsrp等关键基因或信号通路的调节, 其中核心问题是原肠期中胚层如何形成Flk1阳性中胚层细胞及进一步分化成血管内皮祖细胞和成血血管细胞。文章集中评述内皮祖细胞发育、分化及其分子遗传调控机制, 并展望本领域未来发展方向。
The cardiovascular system is one of the first organs formed during embryogenesis. Vessel development involves generating primary vascular endothelial tubes by aggregation of angioblasts (vasculogenesis), creating a vascular network through endothelial sprouting (angiogenesis), and pruning primary vascular tubes by recruiting smooth muscle cells to the vessel walls (vessel maturation). Angioblast, the endothelial progenitor, is generated from hemangioblasts that are derived from the Flk1+ mesodermal cells, or directly from the Flk1+ mesodermal cells. Although several factors such as vegf, flk1, cloche, lycat and estrp are essential for angioblast development, much of the signaling pathways underlying the derivation of angioblasts from the hemangioblasts or Flk1+ mesodermal cells remain unknown. This review will summarize our current knowledge, challenge, and future directions on molecular and cellular mechanisms of endothelial cell develop-ment.
[1] Risau W, Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol, 1995, 11: 73-91.
[2] Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development, 2001, 128(19): 3675-3683.
[3] Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act up-stream of the notch pathway during arterial endothelial differentiation. Dev Cell, 2002, 3(1): 127-136.
[4] You LR, Lin FJ, Lee CT, DeMayo FJ, Tsai MJ, Tsai SY. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature, 2005, 435(7038): 98-104.
[5] Murray PDF. The development in vitro of the blood of the early chick embryo. Proc R Soc London Ser B-Contain Pap A Biol Character, 1932, 111(773): 497-521.
[6] Pardanaud L, Luton D, Prigent M, Bourcheix LM, Catala M, Dieterlen-Lievre F. Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development, 1996, 122(5): 1363-1371.
[7] Xiong JW. Molecular and developmental biology of the hemangioblast. Dev Dyn, 2008, 237(5): 1218-1231.
[8] Eichmann A, Marcelle C, Bréant C, Le Douarin NM. Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech Dev, 1993, 42(1-2): 33-48.
[9] Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 1996, 380(6573): 435-439.
[10] Eichmann A, Corbel C, Nataf V, Vaigot P, Bréant C, Le Douarin NM. Ligand-dependent development of the en-dothelial and hemopoietic lineages from embryonic mesodermal cells expressing vascular endothelial growth factor receptor 2. Proc Natl Acad Sci USA, 1997, 94(10): 5141-5146.
[11] Giles PB, Candy CL, Fleming PA, Owens RW, Argraves WS, Drake CJ. VEGF directs newly gastrulated mesoderm to the endothelial lineage. Dev Biol, 2005, 279(1): 169-178.
[12] Evans MJ, Kaufman MJ. Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981, 292(5819): 154-156.
[13] Vittet D, Prandini MH, Berthier R, Schweitzer A, Mar-tin-Sisteron H, Uzan G, Dejana E. Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Blood, 1996, 88(9): 3424-3431.
[14] Kennedy M, Firpo M, Chol K, Wall C, Robertson S, Kabrun N, Keller G. A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature, 1997, 386(6624): 488-493.
[15] Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development, 1998, 125(4): 725-732.
[16] Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development, 1998, 125(9): 1747-1757.
[17] Chung YS, Zhang WJ, Arentson E, Kingsley PD, Palis J, Choi K. Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression. Development, 2002, 129(23): 5511-5520.
[18] Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature, 2004, 432(7017): 625-630.
[19] Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci USA, 2001, 98(19): 10716-10721.
[20] Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R. Endothelial
